Abstract
BackgroundOne of the hallmarks of Alzheimer's disease, and several other degenerative disorders such as Inclusion Body Myositis, is the abnormal accumulation of amyloid precursor protein (APP) and its proteolytic amyloid peptides. To better understand the pathological consequences of inappropriate APP expression on developing tissues, we generated transgenic flies that express wild-type human APP in the skeletal muscles, and then performed anatomical, electrophysiological, and behavioral analysis of the adults.ResultsWe observed that neither muscle development nor animal longevity was compromised in these transgenic animals. However, human APP expressing adults developed age-dependent defects in both climbing and flying. We could advance or retard the onset of symptoms by rearing animals in vials with different surface properties, suggesting that human APP expression-mediated behavioral defects are influenced by muscle activity. Muscles from transgenic animals did not display protein aggregates or structural abnormalities at the light or transmission electron microscopic levels. In agreement with genetic studies performed with developing mammalian myoblasts, we observed that co-expression of the ubiquitin E3 ligase Parkin could ameliorate human APP-induced defects.ConclusionsThese data suggest that: 1) ectopic expression of human APP in fruit flies leads to age- and activity-dependent behavioral defects without overt changes to muscle development or structure; 2) environmental influences can greatly alter the phenotypic consequences of human APP toxicity; and 3) genetic modifiers of APP-induced pathology can be identified and analyzed in this model.
Highlights
One of the hallmarks of Alzheimer’s disease, and several other degenerative disorders such as Inclusion Body Myositis, is the abnormal accumulation of amyloid precursor protein (APP) and its proteolytic amyloid peptides
Muscle specific expression of human amyloid precursor protein induces an age-dependent reduction in climbing and flying activity In order to study the role of human APP on the development and function of skeletal muscles, we took advantage of a transgenic fly line that expresses hAPP
Under the control of the Upstream Activating Sequence (UAS) [24]. These flies were crossed to a line that expresses the Gal4 transcription factor under the control of the muscle transcription factor Dmef [25], which expresses in all skeletal muscles and a few circadian neurons within the brain [26]
Summary
One of the hallmarks of Alzheimer’s disease, and several other degenerative disorders such as Inclusion Body Myositis, is the abnormal accumulation of amyloid precursor protein (APP) and its proteolytic amyloid peptides. APP became the subject of intense investigation when it was identified as a risk factor for Alzheimer’s disease (AD) [4]. APP can be subjected to combinatorial cleavage by three different intramembrane secretases (a, b, and g) to create a number of smaller peptides [7]. Cleavage by BACE (bsite APP cleaving enzyme) represents a minor pathway in most cell types, except for neurons. Like a-secretase cleavage of APP, the BACE-mediated fragment of APP undergoes further proteolysis by a g-secretase complex to generate small peptides that typically range between 40-44 amino acids, 46 amino acid fragments can be found in skeletal muscles. APP cleavage products are enriched in the brains of some AD patients [8], and exposure to the Ab42 fragment is highly neurotoxic both in vitro and in in vivo animal models [9,10]
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